The Safety and Pharmacokinetics of Carbavance™ (RPX2014/RPX7009) in Subjects With Renal Insufficiency

The worldwide spread of resistance to antibiotics among Gram-negative bacteria, particularly members of the ESKAPE group of pathogens, has resulted in a crisis in the treatment of hospital acquired infections. In particular, the recent dissemination of a serine carbapenemase (e.g., KPC) in Enterobacteriaceae in US hospitals now poses a considerable threat to the carbapenems and other members of the beta-lactam class of antimicrobial agents.

Rempex is developing a fixed combination antibiotic of a carbapenem (RPX2014) plus a new beta-lactamase inhibitor (RPX7009) which has activity against serine beta-lactamases, including KPC. This Phase 1 study will assess the safety, tolerability and pharmacokinetics of intravenous RPX2014 and RPX7009, administered in combination in subjects with varying degrees of renal insufficiency.

Inclusion criteria

• Males and females aged 18 through 80 years of age
• Willing to abstain from alcohol for 48 hours prior to dosing through discharge
• Normal volunteer first matched by age (± 10 years), BMI (± 20%), and gender to the mean values of the moderate renal insufficiency group.
• Have negative test results for HBsAg, anti-HCV antibody and anti-HIV antibody.
• Voluntarily consent to participate in the study
• Sexually abstinent or agree to use two approved methods of contraception.
• Assessment of renal insufficiency for assignment to study groups will be based on measurements of eGFR calculated by the MDRD equation at the Screening Visit to determine eligibility.

Exclusion criteria

• Unstable or new medical conditions (e.g., cardiovascular, respiratory, hepatic, renal, gastrointestinal, autoimmune, endocrine, or neurological disorders)
• Hypersensitivity or idiosyncratic reaction to β-lactam antibiotics (e.g. penicillins, cephalosporins, or carbapenems)
• History of clinically significant seizures, head injury, or meningitis.
• Current evidence or history of malignancy, excluding basal cell carcinoma, in the 2 years prior to Day -1 with no evidence of recurrence.
• Females who are pregnant, lactating, or have a positive pregnancy test
• Previously received any dose of Carbavance (RPX2014/RPX7009).
• Current participation in another investigational study or participation in another investigational clinical study within 30 days prior to the Screening Visit.
• Blood donation or significant blood loss (i.e., > 500 mL) within 56 days prior to Day 1.
• Plasma or platelet donation within 14 days prior to Day -1.
• Any acute illness requiring antibiotic drug therapy within 30 days prior to Day 1 or a febrile illness within 7 days prior to Day 1.
• Vigorous exercise from 48 hours prior to Day -1 until the day of discharge from the study.
• Positive urine drug/alcohol test at the Screening Visit or Day -1
• Concurrent use of medications known to affect the elimination of serum creatinine (e.g., trimethoprim/sulfamethoxazole [Bactrim®] or cimetidine [Tagamet®]) and competitors of renal tubular secretion (e.g., probenecid) within 30 days prior to the first dose of study drug
• Abnormal and clinically significant findings on physical examination, medical history, serum chemistry, hematology, or urinalysis
• Use of any other prescription or nonprescription drugs, vitamins, grapefruit/grapefruit juice or dietary or herbal supplements within 14 days prior to Day -1.

• Oral contraceptives are permitted for birth control.
• Acetaminophen (≤ 1 g/day) and low-dose ASA (i.e., ≤ 325 mg per day) are permitted.
• Currently receives hemodialysis or peritoneal dialysis.